Xanthocillin X Dimethyl Ether Exhibits Anti-Proliferative Effect on Triple-Negative Breast Cancer by Depletion of
Jingjing Du1, Xuening Zhang1, Kaiqiang Guo1
1School of Pharmacy, Faculty of Medicine & State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China.
Abstract:
Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge due to the absence of specific targeted treatments. In this study, we explored the therapeutic potential of xanthocillin X dimethyl ether (XanDME), a naturally occurring isocyanide isolated from the marine fungus Scedosporium apiospermum, on TNBC. To elucidate the underlying mechanism, we initially demonstrated that XanDME directly binds to hemin, the oxidized form of heme, in vitro, corroborating previous reports. This interaction led to the depletion of intracellular regulatory heme. We further established that XanDME translocates into the mitochondria, where it interacts with crucial hemoproteins, namely cytochromes. The binding of XanDME with mitochondrial cytochromes disrupts the electron transport chain (ETC), inhibits the activity of mitochondrial complexes, and inactivates mitochondrial respiration. The inhibitory activity of XanDME on mitochondrial function significantly contributes to its anti-TNBC effects, as observed both in vitro and in vivo. Our study underscores the potential of XanDME against TNBC, warranting further investigations.
Insights
Xanthocillin X dimethyl ether (XanDME) shows promise for treating triple-negative breast cancer (TNBC). This compound targets mitochondrial function, inhibiting cancer cell growth both in lab tests and in living organisms.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies, posing a significant clinical challenge.
- Natural compounds offer potential avenues for novel cancer treatments.
Purpose of the Study:
- To investigate the anti-TNBC therapeutic potential of xanthocillin X dimethyl ether (XanDME).
- To elucidate the molecular mechanisms underlying XanDME's action against TNBC.
Main Methods:
- In vitro binding assays to assess XanDME-hemin interaction.
- Cellular studies to evaluate intracellular heme depletion and mitochondrial translocation.
- Mitochondrial respiration assays to measure electron transport chain (ETC) activity.
- In vitro and in vivo efficacy studies in TNBC models.
Main Results:
- XanDME binds to hemin, leading to intracellular heme depletion.
- XanDME accumulates in mitochondria and interacts with cytochromes.
- Inhibition of mitochondrial complexes and respiration by XanDME.
- Significant anti-TNBC effects observed in vitro and in vivo.
Conclusions:
- XanDME disrupts mitochondrial function, contributing to its anti-TNBC activity.
- XanDME demonstrates therapeutic potential for TNBC.
- Further research into XanDME as a TNBC treatment is warranted.
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